Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0024141 (systemic lupus erythematosus)
 44,322 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Patients with systemic lupus erythematosus (SLE) were recently shown to be defective in costimulatory molecule CD80 (B7-1) expression on antigen-presenting cells. This study was undertaken to further investigate the expression and cytokine regulation of both CD80 and CD86 (B7-2) on monocytes from patients with SLE. Freshly isolated and in vitro cytokine-stimulated peripheral blood mononuclear cells from 13 patients with SLE and 10 healthy subjects were analysed, cytometrically with dual-fluorescence staining, to detect expression of CD80 and CD86 in the CD14+ monocyte population. The results showed that, as in normal individuals, an overwhelming majority (95.62+/-3.54%) of monocytes from patients with SLE expressed the CD86 molecule, but only a few monocytes (5.54+/-4.36%) had detectable CD80 expression. The effects of interleukin-10 (IL-10) on the expression of CD80 and CD86 on monocytes from patients with SLE and normal controls were similar. IL-10 down-regulated the expression of CD86 while it slightly enhanced that of CD80. Interferon-gamma (IFN-gamma) increased both CD80 and CD86 expression on monocytes from both SLE patients and normal groups, albeit less significantly in the former than in the latter, i.e. CD80: 142.84+/-65.99% versus 226.08+/-78.90%, P<0.05; and CD86: 72.55+/-74.23% versus 153.99+/-94.14%, P<0.05, when expressed as percentage modulation. Granulocyte-macrophage colony-stimulating factor (GM-CSF) showed a capacity for up-regulation of CD80 and CD86 expression on monocytes, of a magnitude that was similar both in patients with SLE and in normal subjects. We concluded that CD80 and CD86 were differentially expressed and modulated on monocytes and the defective IFN-gamma-induced up-regulation of CD80 and CD86 expression on SLE monocytes might be a factor in the pathogenesis of SLE.
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PMID:Differential expression and modulation of costimulatory molecules CD80 and CD86 on monocytes from patients with systemic lupus erythematosus. 1002 62

Elevated levels of the cytokine interleukin-10 (IL-10) have been reported in patients with active systemic lupus erythematosus (SLE). Any role for IL-10 in the pathogenesis of SLE is likely to involve the activation of expression of specific genes within its target cells. We have previously reported elevated levels of the 90 000 MW heat-shock protein (hsp 90) and autoantibodies to hsp 90 in patients with SLE. Recent studies have shown that the cytokine IL-6 activates hsp 90 gene expression via specific transcription factors that include STAT-3 (signal transducer and activator of transcription 3). In view of the known role of STAT proteins in IL-10 signalling pathways, we have investigated the effect of IL-10 on hsp 90 gene expression. Here we report that IL-10 enhances the expression of hsp 90 in both a human hepatoma cell line (HepG2) stably expressing the human IL-10 receptor and peripheral blood mononuclear cells (PBMC). In reporter gene assays IL-10 is able to activate both the hsp 90alpha and hsp 90beta promoters directly. Furthermore, a short region of the hsp 90beta promoter which is activated in response to IL-10, contains a STAT-3 binding site. This element but not a mutant derivative unable to bind STAT-3, is able to confer a response to IL-10 on a heterologous promoter. These results may be understood in terms of the shared signalling mechanisms of IL-10 and IL-6 and provide evidence of a role for IL-10 in the overexpression of hsp 90 in SLE, with possible pathological consequences.
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PMID:Interleukin-10 activates heat-shock protein 90beta gene expression. 1044 36

Early onset periodontitis (EOP) is considered to have a substantial genetic basis, although the gene or genes involved have not been elucidated. The aim of the present study was to investigate possible links between generalized EOP (GEOP) and genes regulating expression of the cytokines tumour necrosis factor (TNF) and interleukin-10 (IL-10). Microsatellite marker DNA sequences corresponding to phenotypic variations in cytokine response were analysed. Genotypic variations in cytokine response have been shown in vitro for TNF and IL-10, and specific alleles are implicated in diseases such as systemic lupus erythmatosus (SLE) and rheumatoid arthritis (RA). Two microsatellites at the IL-10 locus, IL10.R and IL10.G, and 1 microsatellite at the TNF locus, TNFa, were typed for 77 GEOP patients in the West of Scotland. Due to the highly polymorphic nature of the microsatellite loci, a statistical comparison with ethnically matched healthy controls (TNFa, n = 91, IL10.R, n = 94, IL10.G, n = 102) was conducted using a Monte Carlo simulation for each marker. No significant differences were observed for any of the 3 markers, although there were possible indications of trends similar to those observed in SLE for the IL10.G marker. In conclusion, no links were found between GEOP and microsatellites at TNFa, IL10.R or IL10.G loci.
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PMID:Analysis of genetic polymorphisms at the interleukin-10 and tumour necrosis factor loci in early-onset periodontitis. 1068 65

In vitro and in vivo, tryptophan degradation was found to be associated with T cell functional loss and tolerance induction. In systemic lupus erythematosus (SLE) besides the Th2-type cytokine interleukin-10, Th1-type cytokines including interferon-gamma (IFN-gamma) are expressed especially during exacerbation of the disease. IFN-gamma stimulates the enzyme indoleamine (2,3)-dioxygenase (IDO) converting tryptophan to the metabolite kynurenine which in macrophages is subsequently degraded to other, partly neurotoxic compounds like quinolinic acid, and finally to nicrotinamides. We measured kynurenine and tryptophan concentrations in the sera of 55 SLE patients. In these patients, the concentrations of tryptophan (median, interquartile range: 53.9, 45.7-64.1 microM) were lower (p < 0.0001), and the kynurenine concentrations (2.45, 1.75-3.40 microM) were increased (p < 0.0005) compared to healthy blood donors (70.0, 63.8-80.6; 1.80, 1.45-2.27 microM, respectively). Also the kynurenine per tryptophan quotients (K/T), which allow to estimate IDO activity, were significantly higher in patients than in normals (0.043, 0.033-0.062 vs. 0.027, 0.021-0.030; p < 0.0001), indicating enhanced IDO-induced tryptophan degradation in SLE. There was no significant relationship between tryptophan, kynurenine and the SLEDAI, and also the correlation of K/T with SLEDAI was rather weak (rs = 0.243, p < 0.05). Higher K/T was found in patients presenting with serositis (p = 0.01), decrease of complement (c3, c4; p < 0.01) and blood count change (anemia, leucopenia, lymphopenia; p = 0.032) than in patients without such disease manifestations. The significant correlation found between K/T and neopterin (rs = 0.808, p < 0.001), a marker of immune activation, points to a role of immune activation to be responsible for tryptophan degradation in SLE patients.
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PMID:Enhanced tryptophan degradation in systemic lupus erythematosus. 1083 18

During the past five years, there has been an intense interest in studying candidate susceptibility genes for systemic lupus erythematosus (SLE). Many such studies have been focused on candidates located on chromosome 1, demonstrating association of certain genetic variants with SLE. Some of the tested candidate genes were chosen because they encode molecules with relevant immunological functions that may play a role in the pathogenesis of SLE. More recently, the identification of genomic segments linked to SLE has suggested novel positional candidate genes. Thus far, there is considerable evidence supporting that multiple genes on this chromosome contribute to the development and expression of SLE. This review highlights the genetic loci located on chromosome 1 that have recently been associated with SLE. These include loci encoding the tumor necrosis factor receptor 2 (TNFR2), complement component C1q, Fcgamma receptors, T cell receptor zeta chain, interleukin-10 (IL-10), poly (ADP-ribose) polymerase (PARP), and HRES-1.
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PMID:Lupus susceptibility genes on human chromosome 1. 1101 22

In systemic lupus erythematosus (SLE), T helper cells exhibit increased and prolonged expression of cell-surface CD40 ligand (CD154), spontaneously overproduce interleukin-10 (IL-10), but underproduce interferon-gamma (IFN-gamma). We tested the hypothesis that the imbalance of these gene products reflects skewed expression of CD154, IL-10, and IFN-gamma genes. Here, we demonstrate that the histone deacetylase inhibitor, trichostatin A, significantly down-regulated CD154 and IL-10 and up-regulated IFN-gamma gene expression in SLE T cells. This reversal corrected the aberrant expression of these gene products, thereby enhancing IFN-gamma production and inhibiting IL-10 and CD154 expression. That trichostatin A can simultaneously reverse the skewed expression of multiple genes implicated in the immunopathogenesis of SLE suggests that this pharmacologic agent may be a candidate for the treatment of this autoimmune disease.
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PMID:Trichostatin A reverses skewed expression of CD154, interleukin-10, and interferon-gamma gene and protein expression in lupus T cells. 1122 90

The future promises good news for the treatment of systemic lupus erythematosus, some of which can already be foreseen. Increased knowledge on genes that participate in the predisposition, pathogenesis, pharmacogenetics of, and protection against this disease may permit intervention at this level. Also, better understanding about the role of sex hormones has allowed trials of weak androgens or prolactin inhibitors. New immunomodulators or immunosuppressors may enable more precise treatment at the immunoregulatory level, and greater knowledge on the disturbance of circuits has already provided hints and even allowed trials of anti-interleukin-10 antibodies, an IL-10 decreasing agent, tolerance-induction strategies or intervention at the level of T cell co-stimulation, as well as immune ablation with subsequent stem cell transplantation. Autoantibodies can be removed, controlled by means of anti-idiotypes, which are blocked from reaching their target antigen or uncoupled from the tissues they have reached. All these treatment strategies will gradually become decanted in order to achieve the optimal treatment of SLE, which may tum out to be its cure.
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PMID:The future of treatment for systemic lupus erythematosus. 1134 23

The meeting consisted of 11 talks that illustrated the complexity of the pathogenetic mechanisms underlying systemic lupus erythematosus and aimed to identify ways in which cytokine modulation might affect those mechanisms. The evidence relating to the involvement of tumour necrosis factor-alpha, interleukin-10 and BLyS in this disease was discussed in particular detail. A final discussion explored the possible ways in which cytokine modulation might lead to new methods of treating systemic lupus erythematosus in the future.
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PMID:Cytokines in systemic lupus erythematosus, London, UK. 1282 45

To investigate the effects of the estrogen receptor-binding molecule bisphenol A (BPA) on murine immune function in vivo, we fed a low dose of 2.5 micro g BPA/kg body weight/day to both normal C57BL/6 and lupus-prone NZB X NZW F(1) (NZB/NZW) 5-week-old mice for 1 week. Analysis of concanavalin A (ConA)-stimulated splenic mononuclear cells by ELISA demonstrated that BPA-fed C57BL/6 males produced, on average, 40% less interferon-gamma (IFN-gamma; p < 0.01) and C57BL/6 females 28% less IFN-gamma (p < 0.05) compared with controls. Treated female NZB/NZW mice were monitored for lupus disease symptoms, defined as proteinuria (> 100 mg/dL albumin in urine for 2 consecutive weeks). Before the development of proteinuria, BPA-fed NZB/NZW mice produced significantly less ConA-stimulated IFN-gamma than did controls and displayed an average reduction of 50% in immunoglobulin G2a (IgG2a) antibody production from lipopolysaccharide (LPS)-stimulated splenocytes (p < 0.05). It is striking that 5-week-old female NZB/NZW mice fed a 7-day low-dose course of BPA developed proteinuria an average of 7 weeks later than did controls. Once proteinuria developed, splenocytes were stimulated with ConA for cytokine analysis. The BPA-fed mice showed a dramatic reduction of 64% in IFN-gamma production and a 32% reduction in ConA-stimulated interleukin-10 (p < 0.05). The long-lasting effects of BPA on IFN-gamma and IgG2a production likely contributed to the increased symptom-free period of the NZB/NZW mice.
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PMID:Effect of bisphenol A on murine immune function: modulation of interferon-gamma, IgG2a, and disease symptoms in NZB X NZW F1 mice. 1464 61

Several lines of evidence suggest interleukin-10 gene (IL-10) is a candidate gene in susceptibility to systemic lupus erythematosus (SLE). We investigated the association of IL-10 promoter single-nucleotide polymorphisms (SNPs) (-3575T/A, -2849G/A, -2763C/A, -1082A/G, -819T/C and -592A/C) and microsatellites (IL10.R, IL10.G) with SLE in 554 Hong Kong Chinese patients and 708 ethnically matched controls. Six haplotypes (hts) were identified from the SNPs. The genotype distribution of the ht1 (T-C-A-T-A), which is associated with low IL-10 production, was different in patients and controls (P=0.009). The homozygous genotype of non-ht1 was significantly increased in patients (P=0.009, odds ratio (OR)=1.80, 95% CI: 1.15-2.82). The frequency of IL10.G4 of IL10.G was also significantly increased in patients (P=0.017, OR=2.53, 95% CI: 1.18-5.40). We found that the homozygous non-ht1 combined with short allele (CA repeat number < or =21) of IL10.G has a dose-dependent effect on SLE susceptibility: non-ht1/non-ht1 with homozygous short allele showed a higher OR (OR=4.11, 95% CI: 1.27-13.2, P=0.018) of association with SLE than the genotype of non-ht1/non-ht1 with heterozygous short/long allele (OR=2.98, 95% CI: 1.26-7.07, P=0.013) and homozygous long allele (OR=1.05, 95% CI: 0.62-1.78, P=0.848). The frequency of non-ht1 was significantly increased in patients with serositis (P<0.0001, OR=2.42, 95% CI: 1.55-3.80). In conclusion, the high expression promoter genotype is associated with SLE in Chinese.
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PMID:Association of interleukin-10 promoter polymorphisms with systemic lupus erythematosus. 1529 21


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